1-(substituted phosphinothioyl, phosphinyl or phosphino)-substituted indole-3-acetic acids

ABSTRACT

Steps 1-3: The reaction is performed in presence of a base such as sodium amide, sodium hydride, phenyl-lithium, tri-phenylmethylsodium, butyl lithium, methyllithium, lithium, diisoproxhylamide, with a substituted phosphonic chloride, substituted phosphonous chloride or substituted phosphinothioyl chloride reagent (see Flow Sheet I compounds B, C &amp; D respectively) in an inert solvent such as benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane, ether, dimethylsulfoxide, xylene, and the like, at temperatures ranging from about 0*C. to 50*C. Of particular preference is the combination of sodium hydride and dimethylformamide at temperatures ranging from about 30*C. to 45*C. under a atmosphere of nitrogen. Representative compounds of this invention are as follow: 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5methoxyindolyl-3-acetic acid 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5-methoxy-6chloro-indolyl-3-acetic acid 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5-methylindolyl3-acetic acid 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5-nitroindolyl3-acetic acid 1-(methyl-4-methylthiophenyl phosphinyl)-2-methyl-5methoxyindolyl-3-acetic acid 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5dimethylaminoindolyl-3-acetic acid 1-(N,N-diethylamino (ethoxy) phosphinyl)-2-methyl-5dimethylaminoindolyl-3-acetic acid 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5-(1pyrrolidino)indolyl-3-acetic acid 1-(4&#39;&#39;-chlorophenyl (ethoxy) phosphinyl)-2-methyl-5-fluoroindoly Novel 1-(substituted phosphinothioyl, phosphinyl or phosphino)substituted indole 3-acetic acids and processes for preparing the same. The 1-(substituted phosphinothioyl, phosphinyl or phosphino)-substituted-indole-3-acetic acids disclosed herein are potent anti-inflammatory, anti-pyretic and analgesic agents. Also included herein are pharmaceutical compositions containing said 1-(substituted phosphinothioyl, phosphinyl or phosphino)substituted-indole-3-acetic acid compounds as an active ingredient, and methods of treating inflammation, fever and pain in patients by administering said compounds. This invention relates to novel 1-(substituted phosphinothioyl, phosphinyl or phosphino)-substituted indole-3-acetic acids and processes for preparing the same. Also included within the scope of the invention are pharmaceutical compositions containing said 1-(substituted phosphinothioyl, phosphinyl or phosphino)substituted indole-3-acetic acid compounds as an active ingredient. The novel 1-(substituted phosphinothioyl, phosphinyl or phosphino)-substituted indole-3-acetic acids of the invention are potent anti-inflammatory, anti-pyretic and analgesic agents which are effective in the method of counteracting inflammation, pain and fever. In the past, numerous compounds have been widely used in the treatment of inflammation, pain and fever. The compounds employed in said treatment have consisted of both steroids and nonsteroids. These compounds have shown side effects ranging from a simple headache to psychic and gastrointestinal disturbances. In a continuous search for potent anti-inflammatory, antipyretic and analgesic agents, we have found a class of novel 1(substituted phosphinothioyl, phosphinyl or phosphino)substituted indole-3-acetic acids which are highly effective in the treatment of inflammation, pain and fever. The novel 1(substituted phosphinothioyl, phosphinyl or phosphino)substituted indole-3-acetic acids are of value in the treatment of arthritic and dermatological disorders of like conditions responsive to anti-inflammatory drugs. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are mainfested. Included within this category are diseases such as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever. As indicated above the compounds utilized in the practice of the invention also possess a useful degree of analgesic and anti-pyretic acitivity. The novel 1-(substituted phosphinothioyl, phosphinyl or phosphino)-substituted indole-3-acetic acid compounds of the invention are represented by the general structure I below: WHEREIN R1 and R2 are each ALKOXY HAVING A MAXIMUM OF SIX CARBON ATOMS SUCH AS METHOXY, ETHOXY, ISOPROPYLOXY, BUTOXY AND THE LIKE, ALKYL HAVING A MAXIMUM OF SIX CARBON ATOMS SUCH AS METHYL, PROPYL, ETHYL, T-BUTYL AND THE LIKE, ALKYLAMINO HAVING A MAXIMUM OF SIX CARBON ATOMS SUCH AS METHYLAMINO, DIMETHYLAMINO, BUTYLAMINO, DIETHYLAMINO, METHYLETHYLAMINO AND THE LIKE, ALKENYLAMINO HAVING A MAXIMUM OF SIX CARBON ATOMS SUCH AS DIBUTENYLAMINO, PROPENYLAMINO, DIPENTENYLAMINO, DIETHENYLAMINO, DIPROPENYLAMINO AND THE LIKE, ARYLAMINO HAVING A MAXIMUM OF EIGHT CARBON ATOMS SUCH AS ANILINO, O,M OR P-TOLYLAMINO, ANISIDINO AND THE LIKE, OA wherein A is a cation such as sodium, potassium, calcium, lithium, magnesium and the like, haloaryl having a maximum of eight carbon atoms such as chlorophenyl, chloromethylphenyl, fluorophenyl, bromophenyl, and the like, haloaralkyl having a maximum of eight carbon atoms such as o,m or p-chlorobenzyl, o,m or p-fluorobenzyl o,m or p-bromobenzyl and the like, aryloxy having a maximum of eight carbon atoms such as phenoxy, o,m or p-halophenoxy, o,m or p-tolyloxy, o,m or p-methoxyphenoxy and the like or aralkyloxy having a maximum of nine carbon atoms such as benzyloxy, phenethyloxy, o,m or p-methoxybenzyloxy, o,m or p-methylbenzyloxy and the like; R3 is hydrogen or alkyl having a maximum of six carbon atoms such as methyl, ethyl, isopropyl, butyl, and the like; R4 is hydrogen or alkyl having a maximum of six carbon atoms such as methyl, ethyl, propyl, butyl, and the like; R5 is hydrogen, alkyl having a maximum of six carbon atoms such as methyl, ethyl, propyl, butyl, and the like, alkoxy having a maximum of six carbon atoms such as methoxy, ethoxy, butoxy, isopropoxy, and the like, nitro, alkylamino having a maximum of six carbon atoms such as ethylamino, dimethylamino, propylamino, diethylamino, methylethylamino, butylamino, diisopropylamino, and the like, alkanoyl having a maximum of four carbon atoms such as acetyl, propionyl, butyryl, and the like, N-azepino, N-pyrrolidino, 4-methyl-1-piperazinyl, N-morpholino, cyano, halogen, such as, chlorine, fluorine, bromine, and the like or alkenyl having a maximum of six carbon atoms such as vinyl, allyl, propenyl, butenyl, and the like; R6 is hydrogen, halogen, such as, chlorine, fluorine, bromine, and the like alkoxy having a maximum of six carbon atoms such as, methoxy, ethoxy, isopropoxy, butoxy, and the like or alkyl having a maximum of six carbon atoms such as, methyl, ethyl, isopropyl, butyl, and the like; X is oxygen or sulfur; n is an integer equal to 0 or 1; and M is hydroxy, alkoxy having a maximum of six carbon atoms such as, methoxy, ethoxy, t-butoxy and the like, aralkyloxy having a maximum of nine carbon atoms such as, benzyloxy, o,m or p-methylbenzyloxy, o,m or p-methoxybenzyloxy, and the like or OZ where Z is a cation, such as, sodium, potassium, aluminum, magnesium, barium, calcium, and the like. The preferred compounds of this invention are those compounds represented by the above general structure wherein R1 and R2 are selected from the group consisting of alkoxy, alkylamino, OA wherein A is a cation, arylamino, haloaryl and haloaralkyl; R3 is alkyl; R4 is hydrogen; R5 is selected from the group consisting of alkoxy, alkylamino, N-azepino, N-pyrrolidino, 4-methyl-1piperazinyl, N-morpholino, cyano and halogen; R6 is hydrogen; X is oxygen; n is 1; and M is selected from the group consisting of hydroxy and alkoxy. The most preferred compounds of this invention are represented wherein R1 and R2 are selected from the group consisting of alkoxy, OA wherein A is a cation, haloaryl and haloaralkyl; R3 is alkyl; R4 is hydrogen; R5 is alkoxy, alkylamino, Halogen and N-pyrrolidino; R6 is hydrogen; X is oxygen; n is 1; and M is hydroxy. The pharmaceutically acceptable salts of the compounds disclosed herein are to be considered within the scope of the invention. Representative examples of said pharmaceutically acceptable salts are alkali metals such as sodium, potassium, and the like, and alkaline earth metals such as barium, calcium, magnesium, and the like. This invention may be better understood from the details shown below. The novel compounds of the invention are prepared by employing 2,5-disubstituted-indole-3-acetic acid and derivatives thereof (A) as the starting material wherein R3, R4, R5, and R6 are as defined above and M is other than hydroxy. The anion of starting material (A) is treated with a substituted phosphonic chloride reagent (B) wherein R1 and R2 are as defined above to obtain compound (E), 1-(substituted phosphinyl)-2,5-disubstitutedindole-3-acetic acid or derivative thereof wherein n is 1 and X is oxygen. To obtain the novel 1-(substituted phosphino)-2,5disbustituted-indole-3-acetic acid compounds or derivatives thereof (E), the anion of starting material (A) is treated with a substituted phosphonous chloride reagent (C). The novel 1(substituted phosphinothioyl)-2,5-disubstituted-indole-3-acetic acid compounds or derivatives thereof (E) wherein n is 1 and X is sulfur, are obtained by treating the anion of starting material (A), 2,5-disubstituted-indole-3-acetic acid or derivative thereof with a substituted phosphinothioyl reagent (D). When R1 or R2 in compound (E) is other than OA wherein A is a cation, said compound (E) is then treated with an aqueous base (alkali, alkaline and etc.) to obtain the mono or di-phosphate salt of the corresponding indole-3-acetic acid derivative. Flow Sheet I below represents the general reaction sequence for the preparation of the novel compounds of this invention.

United States Patent 11 1 Hannah Aug. 26, 1975 l-[SUBSTITUTED PHOSPHINOTHIOYL,

PHOSPHINYL OR PHOSPHINO1-SUBSTITUTEI) INDOLE-3-ACETIC ACIDS [52] US. Cl. 260132612 R; 26U/326.l3 R; 260[326.|4 R; 260/268 TR; 260/247.l B2 260/2472 R; 260/2472 B; 260/268 BC;

51 int. cm c071) 209/18; (5071) 209/20; A61 K 31/675 58 Field of Search .1 260/326.l3 R, 326.12 R

Primary Examiner-Elbert L. Roberts Assistant Examiner-S. P. Williams Attorney, Agent, or Firm-Harry E. Westlake, Jr.; William H. Nicholson [57] ABSTRACT Novel l-[substituted phosphinothioyl, phosphinyl or phosphino1-substituted indole 3-acetic acids and processes for preparing the same. The l-[substituted phosphinothioyl, phosphinyl or phosphino1- substituted-indole-3-acetic acids disclosed herein are potent anti-inflammatory, anti-pyretic and analgesic agents. Also included herein are pharmaceutical compositions containing said l-[substituted phosphinothioyl, phosphinyl or phosphino]-substituted-indole-3- acetic acid compounds as an active ingredient, and methods of treating inflammation, fever and pain in patients hy administering said compounds.

6 Claims, N0 Drawings 1 l-[SUBSTITUTED PHOSPHINOTHIOYL, PHOSPHINYL OR PHOSPHIN01-SUBSTITUTED INDOLE-3-ACETIC ACIDS This invention relates to novel l-[substituted phosphinothioyl, phosphinyl or phosphinol-substituted indole-3-acetic acids and processes for preparing the same. Also included within the scope of the invention are pharmaceutical compositions containing said 1- [substituted phosphinothioyl, phosphinyl or phosphino]-substituted indole-3-acetic acid compounds as an active ingredient. The novel l-[substituted phosphinothioyl, phosphinyl or phosphinol-substituted indole-3-acetic acids of the invention are potent anti-inflammatory, anti-pyretic and analgesic agents which are effective in the method of counteracting inflammation, pain and fever.

in the past, numerous compounds have been widely used in the treatment of inflammation, pain and fever. The compounds employed in said treatment have consisted of both steroids and non-steroids. These compounds have shown side effects ranging from a simple headache to psychic and gastrointestinal disturbances.

In a continuous search for potent anti-inflammatory, anti-pyretic and analgesic agents, we have found a class of novel l-[substituted phosphinothioyl, phosphinyl or phosphinol-substituted indole'3-acetic acids which are highly effective in the treatment of inflammation, pain and fever. The novel l-[substituted phosphinothioyl, phosphinyl or phosphino1-substituted indole-3-acetic acids are of value in the treatment of arthritic and dermatological disorders of like conditions responsive to anti-inflammatory drugs. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are mainfested. Included within this category are diseases such as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever. As indicated above the compounds utilized in the practice of the invention also possess a useful degree of analgesic and antipyretic acitivity.

The novel l-[substituted phosphinothioyl, phosphinyl or phosphinol-substituted indole-3-acetic acid compounds of the invention are represented by the general structure I below:

/ cncom I ll R6 R3 1 R (X) n l 1 wherein R, and R are each alkoxy having a maximum of SIX carbon atoms such methyl, P PYL ethyl, t-butyl and the like, alkylamino having a maximum of six carbon atoms such as methylamino, dimethylamino, butylamino, diethylamino, methylethylamino and the like, alkenylamino having a maximum of six carbon atoms such as dibutenylamino, propenylamino, dipentenylamino, diethenylamino, dipropenylamino and the like, arylamino having a maximum of eight carbon atoms such as anilino, o,m or p-tolylamino, anisidino and the like, 0A wherein A is a cation such as sodium, potassium, calcium, lithium, magnesium and the like, haloaryl having a maximum of eight carbon atoms such as chlorophenyl, chloromethylphenyl, fluorophenyl, bromophenyl, and the like, haloaralkyl having a maximum of eight carbon atoms such as o,m or p-chlorobenzyl, o,m or p-fluorobenzyl o,m or p-bromobenzyl and the like, aryloxy having a maximum of eight carbon atoms such as phenoxy, o,m or p-halophenoxy, o,m or p-tolyloxy, o,m or p-methoxyphenoxy and the like or aralkyloxy having a maximum of nine carbon atoms such as benzyloxy, phenethyloxy, o,m or p-methoxybenzyloxy, o,m or p-methylbenzyloxy and the like; R3 is hydrogen or alkyl having a maximum of six carbon atoms such as methyl, ethyl, isopropyl, butyl, and the like; R is hydrogen or alkyl having a maximum of six carbon atoms such as methyl, ethyl, P PY butyl, and the like; R5 is hydrogen, alkyl having a maximum of six carbon atoms such as methyl, ethyl, P PYL butyl, and the like, alkoxy having a maximum of six carbon atoms such as methoxy, ethoxy, butoxy, isopropoxy, and the like, nitro, alkylamino having a maximum of six carbon atoms such as ethylamino, dimethylamino, propylamino, diethylamino, methylethylamino, butylamino, diisopropylamino, and the like, alkanoyl having a maximum of four carbon atoms such as acetyl, propionyl, butyryl, and the like, N-azepino, N-pyrrolidino, 4-methyl-l-piperazinyl, N-morpholino, cyano, halogen, such as,

chlorine, fluorine, bromine, and the like or alkenyl having a maximum of six carbon such as vinyl, ally], propenyl, butenyl, and the like; R3 is hydrogen, halogen, such as,

chlorine, fluorine, bromine, and the like alkoxy having a maximum of six carbon atoms such as, methoxy, ethoxy, isopropoxy, butoxy, and the like or alkyl having a maximum of six carbon atoms such as, methyl, ethyl, isopropyl, butyl, and the 'like; X is oxygen or sulfur; n is an integer equal to or 1; and

atoms M is hydroxy,

alkoxy having a maximum of six carbon atoms such as. methoxy, cthoxy, t-butoxy and the like,

aralkyloxy having a maximum of nine carbon atoms such as, benzyloxy, 0,m or p-methylbenzyloxy, o,m or p-methoxybenzyloxy, and the like or OZ where Z is a cation, such as,

sodium,

potassium, aluminum, magnesium,

barium,

calcium, and the like.

The preferred compounds of this invention are those compounds represented by the above general structure wherein R, and R, are selected from the group consisting of alkoxy, alkylamino, 0A wherein A is a cation, arylamino, haloaryl and haloaralkyl; R is alkyl; R is hydrogen; R is selected from the group consisting of alkoxy, alkylamino, N-azepino, N-pyrrolidino, 4-methyll-piperazinyl, N-morpholino, cyano and halogen; R, is hydrogen; X is oxygen; n is l; and M is selected from the group consisting of hydroxy and alkoxy. The most preferred compounds of this invention are represented wherein R, and R, are selected from the group consisting of alkoxy, 0A wherein A is a cation, haloaryl and haloaralkyl; R, is alkyl; R, is hydrogen; R is alkoxy, alkylamino, halogen and N-pyrrolidino; R, is hydrogen; X is oxygen; :1 is l; and M is hydroxy.

The pharmaceutically acceptable salts of the compounds disclosed herein are to be considered within the scope of the invention. Representative examples of said pharmaceutically acceptable salts are alkali metals such as sodium, potassium, and the like, and alkaline earth metals such as barium, calcium, magnesium, and.

the like.

This invention may be better understood from the details shown below.

The novel compounds of the invention are prepared by employing 2,S-disubstituted-indole-3-acetic acid and derivatives thereof (A) as the starting material wherein R R R and R, are as defined above and M is other than hydroxy. The anion of starting material (A) is treated with a substituted phosphonic chloride reagent (B) wherein R, and R, are as defined above to obtain compound (E), l-[substituted phosphinyl]-2,5- disubstituted-indole-3-acetic acid or derivative thereof wherein n is 1 and X is oxygen. To obtain the novel I- [substituted phosphinol- 2,S-disbustituted-indole-3-acetic acid compounds or derivatives thereof (E), the anion of starting material (A) is treated with a substituted phosphonous chloride reagent (C). The novel l-lsubstituted phosphinothioyl]-2,5-disubstituted-indole3-acetic acid compounds or derivatives thereof (E) wherein n is l and X is sulfur, are obtained by treating the anion of starting material (A), 2,5-disubstituted-indole-3-acetic acid or derivative thereof with a substituted phosphinothioyl reagent (D). When R, or R in compound (E) is other than 0A wherein A is a cation, said compound (E) is then treated with an aqueous base (alkali, alkaline and etc.)

to obtain the mono or di-phosphate salt of the corre sponding indole-3-acetic acid derivative. Flow Sheet 1 below represents the general reaction sequence for the preparation of the novel compounds of this invention.

{12w Sheet I Y cucom R6 N: :R3

R R4 5 i -CHCOM R6 u R3 c1 c1 c1 3 l i P P P 0; R 12 R 5 R Reactions and Conditions Steps 1-3:

The reaction is performed in presence of a base such as sodium amide, sodium hydride, phenyl-lithium. :ri-phenylmethylsodium, butyl lithium. methyllithium. ,ithium, diisoproxhylamide, with a substituted phosphonic chloride, substituted phosphonous chloride or substituted phosphinothioyl chloride reagent (see Flow Sheet I compounds 8, C & D respectively) in an inert solvent such as benzene, toluene, dimethylformamide, tetrahydrofuran, dioxane, ether, dimethylsulfoxide, xylene, and the like, at temperatures ranging from about C. to 50C. Of particular preference is the combination of sodium hydride and dimethylformamide at temperatures ranging from about 30C. to 45C. under a atmosphere of nitrogen.

Representative compounds of this invention are as Follow:

l-[4'-chlorophenyl (ethoxy) phosphinyll-Z-methyl- S-methoxyindolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphinyl]-2-methyl- -methoxy--chloro-indolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphinyl1-2-methyl- 5-methylindolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) 5-nitroindolyl-3-acetic acid 1-[methyl-4-methylthiophenyl phosphinyH-Z-methyl- S-methoxyindolyl-3-acetic acid 1-[4'-chlorophenyl (ethoxy) phosphinyll-Z-methyl- 5-dimethylaminoindolyl-3-acetic acid l-[N,N-diethylamin0 (ethoxy) phosphinyll-Z-methyl- 5-dimethylaminoindolyl-Ii-acetic acid l-[4-chlorophenyl (ethoxy) phosphinyl1-2-methyl- 5-[ l-pyrrolidino)indolyl-3acetic acid l-[4-chlorophenyl (ethoxy) phosphinyH-Z-methyL 5-fluoroindolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphinyl1-2-methyl- 5-acetylindolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) 5-cyanoindolyl-3-acetic acid l-[4' chlorophenyl (ethoxy) phosphinyl]-2-methyl- 5-propenylindolyl-3-acetic acid l-(4-chlorophenyl (ethoxy) phosphino1-2-methyl- 5-methylindolyl-3-acetic acid l-[4"chlorophenyl (ethoxy) phosphinol-Z-methyl-S- nitroindolyl-3-acetic acid l-[di-isopropoxy phosphino]-2-methyl-S-nitroindolyl- 3-acetic acid l-[4-chlorophenyl (ethoxy) phosphinol-Z-rnethyL 5-dimethylaminoindolyl3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphinol-2-methyl- 5-( l-pyrrolidino)indolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphino1-2-methyl- S-fluoroindolyl-S-acetic acid l-[4'-chlorophenyl (ethoxy) 5-acetylindolyl-3-acetic acid l-[4 chlorophenyl (ethoxy) phosphino1-2-methyl- 5-propenylindolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphinothioyll-Z- methyl-5-methoxyindolyl-3-acetic acid l-[4'-chl0rophenyl (ethoxy) phosphinothioyl1-2- methyl-S-nitroindolyl-3-acetic acid l-[4-methylthiophenyl (ethoxy) phosphinothioyll- 2-methyl-5-nitroindolyl-3acetic acid phosphinyll-Z-methylphosphinyl ]-2 methylph0sphino]-2-methyl- 8 l-[4'-chlorophenyl (ethoxy) phosphinothioyll-2- methyl-5-dimethylaminoindolyl-3-acetic acid l-[0-ethyl-N,N,-diethylamino-phosphinothioyll-2- methyl-S-dimethylaminoindolyl-3-acetic acid l-[4-chlorophenyl (ethoxy) phosphinothioyll-Z- methyl-5-( l-pyrrolidino) indolyl-3-acetic acid l-[4-chlorophenyl (ethoxy) phosphinothioyl1-2- methyl-5-fluoroindolyl-3-acetic acid 1-[4'-chlorophenyl (ethoxy) phosphinothioyH-Z- methyl-5-acetylindolyl-3-acetic acid 1-l4'-chlorophenyl (ethoxy) phosphinothioylJ-Z- methyl-5-cyanoindolyl-3-acetic acid l-[4'-chlorophenyl (ethoxy) phosphinothioyll-Z- methyl-5-propenylindolyl-3-acetic acid l-[3-chlorophenyl (ethoxy) phosphinyl1-2-methyl- 5-methoxyindolyl-3-acetic acid l-[ethoxy (hydroxy) phosphinyll-2-methyl-5- methoxyindolyl-S-acetic acid disodium salt l -[ethoxy (hydroxy) phosphinyl1-2-methyl-S- dimethylaminoindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinyl]-2-methyl-5-( lpyrrolidino)-indolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinyl1-2-methyl-5- fluoroindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinyl1-2-methyl-5- propenylindolyl-3-acetic acid disodium salt l -[ethoxy (hydroxy) phosphinyl ]2-ethyl-S- methoxyindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinol-Z-methyl-S- methoxyindolyl 3 acetic acid disodium salt l-[ethoxy (hydroxy) phosphino1-2-methyl-5- dimethylaminoindolyl-3acetic acid disodium salt l-[ethoxy (hydroxy) phosphino]-2-methyl-5-( lpyrrolidino) indolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinol-2-methyl-5' fluoroindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphino1-2-methyl-5- propenylindolyl-3-acetic acid disodium salt l ethoxy (hydroxy) phosphinol-Z-ethyLS- methoxyindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinothioyl]-2-methyl-5- methoxyindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinothioyl]-2-methyl-5- dimethylaminoindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinothioyl]-2-methyl-5- (l-pyrrolidino) indolyl-3-acetic acid disodium salt I-[ethoxy (hydroxy) phosphinothioyl]-2-methyl-S- fluoroindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinothioyl]-2-methyl-5- propenylindolyl-3-acetic acid disodium salt l-[ethoxy (hydroxy) phosphinothioyl 2-ethyl-5- methoxyindolyl-3-acetic acid sodium salt 1-[4-chlorophenyl (hydroxy) phosphinyl]2-methyl- 5-methylindolyl-3-acetic acid sodium salt and l-[4'-chlorophenyl (hydroxy) phosphinothioyll- 2-methyiindolyl-3-acetic acid sodium salt The compounds of this invention are administered orally, topically, intravenously, or intramuscularly as a phosphate salt in the treatment of inflammation, fever and pain. Of particular preference is the oral form ranging from 1 to 2,000 mg./kg. of body weight per day. Of preference is l0-500 mg./kg. of body weight per day for varying periods of treatment as required. Comparable amounts ofthc compounds may be admin istered in topical or parenteral forms.

For these purposes the compounds of the invention may be administered orally. topically, and parenterally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral" as used herein includes intravenous or intramuscular. In addition to the treatment of warm-blooded animals such as mice, rats, horses, dogs cats, etc., the compounds of the invention are effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredients may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non toxic phannaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintergrating agents, for example, maize starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or tale. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example arachis oil, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agent, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, so dium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan monooleate. The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or npropyl p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oils, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth, naturally-occurring phosphatides, for example, soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan mono-oleate, and condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

For intravenous and intramuscular administrations, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringers solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic monoor di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 5 mg. to ID grams of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about percent of the total composition. Dosage unit forms will generally contain between from about mg. to about 1.75 g. of the active ingredient. Comlarable amounts of the compounds may be adminisered in topical or parenteral forms.

It will be understood, however, that the specific dose evel for any particular patient will depend upon a varity of factors including the activity of the specific com ound employed, the age, body weight, general health, ex, diet, time of administration, route of administralon, rate of excretion, drug combination and the sever- :y of the particular disease undergoing therapy.

The starting materials employed in the invention are ,5-disubstituted-indole-3-acetic acid, substituted hosphonic chloride, substituted phosphonous chloride nd substituted phosphinothioyl chloride which are 1own in Flow Sheet 1 as compounds A, B, C and D, re- Jectively. Starting material (A) is known and proesses for its preparation can be found in the literature. or example, see US. Patent No. 3,161,654. Also startig materials (B,C, and D) and known and processes )r its preparation can be found in the literature. For xample, see HoubenWeyl 12-1, 307 and 368-393 1963); Houben-Weyl 12-2, 98, 280-291, 386 and -447 (1964); and Monatshefte Fur Chemie, 96, 936-42 (1965).

The following examples illustrate the preparation of ie various l-[substituted phosphino, phosphinyl or phsphinothioyl]-indole-3-acetic acid and derivative iereof described herein as anti-inflammatory, antiyretic and analgesic agents. The examples should be )nstrued as an illustration of the invention rather than limitation thereof.

EXAMPLE 1 Z-Fluorophenyl phosphonic dichloride 2-Fluorophenyl phosphonic acid (17.6 g, 0.1 mole) intimately mixed with phosphonous pentachloride 13.8 g, 0.21 mole) with care to exclude moisture. A gorous reaction is initiated by careful warming of the ixture. After the resulting reaction has ceased, the ixture is heated to 80 until a clear solution is obined. Fractional distillation removes the phospho- )IJS oxychloride formed and yields 2-fluorophenyllosphonic dichloride.

EXAMPLE 2 Ethyl 2-fluorophenylphosphonochloridate To a solution of 2-fluorophenylphosphonic dichlole (22.2 g, 0.1 mole) in dry benzene (100 ml) is vded drop wise with agitation a solution containing hanol (4.61 g, 0.1 mole) with pyridine (7.91 g, 0.1 ole) in ml. of benzene. The resulting mixture is ated to reflux for minutes in order to complete the action. This mixture is then cooled to room temperare, filtered and the filtrate is evaporated to obtain 1yl 2-tluorophenyl-phosphonochloridate.

When methanol, propanol, isopropanol, phenol or nzyl alcohol is substituted for ethanol, there is obned methyl, propyl, isopropyl, phenyl or benzyl 2- orophenylphosphonochloridate.

EXAMPLE 3 Ethyl 4-chlorophenylphosphonochloridate ["o a solution of 4-chlorophenylphosphonic dichloe (19.85 g, 0.1 mole) in dry benzene (100 ml) is :led drop wise with agitation a solution of ethanol 61 g, 0.1 mole) and pyridine (7.91 g, 0.1 mole) in ml. of benzene. The mixture is heated to reflux and maintained for 30 minutes to complete the reaction. Said mixture is then cooled to room temperature, filtered and the filtrate evaporated at /0.1 mm. to obtain ethyl 4-chlorophenylphosphonochloridate.

When methanol, propanol, isopropanol, phenol or benzyl alcohol is substituted for ethanol, there is obtained methyl, propyl, isopropyl, phenyl, or benzyl 4- chlorophenylphosphonochloridate.

EXAMPLE 4 lsopropyl 4-ch1orophenylphosphonochloridite To a solution of 4-chlorophenylphosphonous dichloride (18.25 g, 0.1 mole) in hexane (100 ml) at 0 in a dry nitrogen atmosphere is added dropwise with agitation a solution of isopropanol (6.01 g, 0.1 mole) and N,N diethylamine (14.92 g 0.1 mole) in 20 ml of hexane. This mixture is allowed to warm to room temperature within approximately an hour period and the filtrate evaporated at reduced pressure. Fractional distillation of the residue at reduced pressure yields isopropyl 4-chlorophenylphosphonochloridite.

When ethanol, butanol, phenol or benzyl alcohol is substituted for isopropanol, there is obtained the corresponding ethyl, butyl, phenyl or benzyl 4-chlorophenylphosphonochloridite.

EXAMPLE 5 Ethyl 4-chlorophenyl phosphorochloridite distillation of the residue at reduced pressure yields ethyl 4-chlorophenyl phosphorochloridite.

When phenol, benzyl alcohol, o,m or p-cresol, o,m or p-bromophenol is substituted for 4-chlorophenol, there is obtained the corresponding ethyl, phenyl, benzyl, o,m or p-methylphenyl, o,m or p-bromophenylphosphorochloridite.

EXAMPLE 6 Ethyl N-4-chlorophenylphosphoramidochloridite To a solution of ethyl phosphorodichloridite (14.70 g., 0.1 mole) in dry benzene (100 ml.) at room temperature is added dropwise with agitation to a solution of 4-chloroaniline (25.52 g., 0.2 mole) in 20 ml. dry benzene. The resulting mixture is stirred at room temperature for approximately 2 hours filtered, and the filtrate evaporated. Fractional distillation of the residue at reduced pressure yields ethyl N-4-chlorophenylphosphoramidochloridite.

When methylamine, o,m or p-methoxybenzylamine, o,m or p-halobenzylamine, allylamine or dibutenylamine is substituted for 4-chloroaniline, there is obtained the corresponding ethyl N-methyl, o,m or pmethoxybenzyl, o,m or phalobenzyl, allyl or dibutenylphosphoramidochloridite.

EXAMPLE 7 Tert-butyl l-[4'-chlorophenyl(ethoxy )phosphinyl I-S-methoxy-Z- methyl-3-indolylacetate 57% Sodium hydride oil dispersion (0.44 g., 10.5 m. mole) is added to a solution of tert-butyl S-methoxy-Z- methyl-3-indolylacetate (2.75 g., 10.0 m. mole) in dry dimethyl formamide (15 ml.) with stirring and at a rate to keep the temperature 35-40. The mixture is stirred at 40 for 15 minutes to complete anion formation, then cooled to room temperature and ethyl 4- chlorophenylphosphonochloridate (2.63 g., 11.0 m. mole) added at a rate to maintain a temperature not higher than 40. Stirring is continued at room temperature for 24 hours in an atmosphere of dry nitrogen, then the solvent is removed in a rotary evaporator at 40/0.l mm. and the crude product purified by chromatography over silica gel, yields tert-butyl 1-[4'- chlorophenyl(ethoxy)phosphinyll-S-methoxy-Z- methyl-3-indolylacetate. When ethyl 2-fluorophenylphosphonochloridate,

methyl 4methylthiophenylphosphonochloridate,

isopropyl 4-chlorophenylphosphonochloridite di-isopropyl phosphorochloridate ethyl N,N-diethylphosphoramidochloridate ethyl 4-chlorophenylphosphorochloridite ethyl N-4-chlorophenylphosphoramidochloridite diisopropyl phosphorochloridothionate or N,N-dimethyl o-ethylphosphoramidochloridothionate tert-butyl 1-[2'-fluorophenyl(ethoxy)phosphinyl]-5- methoxy-2-methyl-3-indolylacetate tert-butyl l-[4'-methylthiophenyl(ethoxy)phosphinyll- 5-methoxy-2-methyl-3-indolylacetate tert-butyl isopropyl l-[4'-chlorophenylphosphino]-5- methyl'3-indolylacetate,

tert-butyl l-[diisopropoxyphosphinyl]-5-methoxy-2- methyl-B-indolylacetate,

tert-butyl l-[N.N-diethylamino(ethoxy)phosphinyl]-5- methoxy-2-methyl-3-indolylacetate,

tert-butyl l-[4'-chlorophenyl(ethoxy)phosphinol-S- methoxy-2-methyl-3-indolylacetate,

tert-butyl l-[4 chlorophenylamino(ethoxy)phosphinoj-S-methoxy- 2-methyl-3-indolylacetate tert-butyl l-[4'- chlorophenyl( ethoxy )phosphinothioyl l-5-methoy-2 methyl-3-indolylacetate tert-butyl 1dimethylamino(ethoxy)phosphinothioyl-S- methoxy-2-methyl-3-indolylacetate, respectively.

EXAMPLE 8 Benzyl 1-[ 4'-chlorophenyl(ethoxy)phosphinyl ]-5-methoxy-2- methyl-3-indolylacetate 57% Sodium hydride oil dispersion (0.44 g.. 10.5 m. mole) is added to a solution of benzyl 5-methoxy-2- methyl- 3-indolylacetate (3.09 g., 10.0 m. mole) in dry dimethyl formamide ml.) with stirring and at a rate to keep the temperature 3540. The mixture is stirred at 40 for 15 minutes to complete anion formation. then cooled to room temperature and ethyl 4- chlorophenylphosphonochloridate (2.63 g.. 1 1.0 m. mole) added at a rate to maintain a temperature not higher than 40. Stirring is continued at room temperature for 24 hours in an atomosphere of dry nitrogen,

then the solvent was removed in a rotary evaporator at 40/0.1 mm. and the crude product purified by chromatography over silica gel, yielding benzyl 1-[4'- chlorophenyl(ethoxy)phosphinyl1-5-methoxy-4- methoyl-3-indolylacetate.

When

ethyl 2-fluorophenylphosphonochloridate methyl 4-methylthiophenylphosphonochloridate isopropyl 4-chlorophenylphosphonochloridite diisopropyl phosphorochloridate ethyl N,N-diethyl phosphoramidochloridate ethyl 4-chlorophenylphosphorochloridite ethyl N-4-chlorophenylphosphoramidochloridite diisopropyl phosphorochloridothionate or N,N-dimethyl o-ethyl phosphoramidochloridothionate is substituted for ethyl 4-chlorophenylphosphonochloridate, there is obtained:

EXAMPLE 9 The procedure of example 7 is repeated except that the starting material is tert-butyl-S-methoxy-2-methyl-3-indolylpropionate tert-butyl-S-fluoro-2-methyl3-indolylacetate tert-buty1-6-chloro-2-methyl-3-indolylacetate tert-butyl 6-chloro-5-methoxy-2-methyl-3- indolylacetate tert-butyl-2-methyl-S-dimethylamino-S-indolylacetate tert-butyl-2-methyl-5-( l-pyrrolidino )-3-indolylacetate tert-butyl-Z-methyl-S-fluoro-3-indolylacetate tert-butyl-Z-methyl-5-cyano3-indolylacetate tert-butyl-2-methyl-5-propenyl-3-indolylacetate or tert-butyl-Z-methyl-5-nitro-3-indo1ylacetate,

is substituted for tert-butyl-S-methyl-2-methyl-3- indolylacetate. Using the same reaction and conditions. there is obtained:

tert-butyl-l [4'-chlorophenyl(ethoxy)phosphinyl]-5- methoxy-2-methyl-3-indolypropionate tert-butyl-l 14'-chlorophenyl(ethoxy)phosphinyl]-S- fluoro-2-methyl-3-indolylacetate tert-butyl-l l4'-chlorophenyl(ethoxy)phosphinyl]-6- chloro-2-methyl-3-indolylacetate tert-butyll -{4-chlorophenyl( ethoxy)phosphinyl]-6 chloro-5-methoxy-2-methyl-3-indolylacetate tert-butyll -[4-chlorophenyl( ethoxy )phosphinyH-Z- methyl-S-dimethylamino-3-indolylacetate tert-butyl-l [4'-chlorophenyl(ethoxy)phosphinyl]-2- methyl-5-( l -pyrrolidino)-3-indolylacetate tert-butyll 4'-chlorophenyl(ethoxy )phosphinyl]-2- methyl-5-fluoro-3-indolylacetate tert-butyll -[4'-chlorophenyl( ethoxy)phosphinyl]-2- methyl-5-cyano-3-indolylacetate tert-butyll -[4'-chlorophenyl( ethoxy )phosphinylj-Z- methyl-S-propenyl-3-indolylacetate or tert-butyll -[4'-chlorophenyl( ethoxy )phosphinyH-Z- methyl-S-nitro-3-indolylacetate.

EXAMPLE l-[4'-chlorophenyl(hydroxy)phosphinyll-S-mthoxy- 2-methylindolyl-3-acetic acid mono sodium salt A. Tert-butyll -[chlorophenyl(hydroxy )phosphinyl methoxy-Z-methyl 3'indolylacetate mono sodium salt Tert-butyll -[4'-chlorophenyl( ethoxy)phosphinyl 5-methoxy-2-methyl-3-indolylacetate, (2.39 g. 50.0 m. nole) is dissolved in a hot solution of dried sodium iolide (0.75 g. 5.0 m. mole) in freshly distilled methyl- :thyl ketone (25 ml.) The solution is stirred and heated mder reflux in a dry nitrogen atmosphere for 3 hours, hus forming a precipitate of the desired product. Filration, washing with acetone and drying in vacuo leilds tert-butyll -[4'- :hlorophenyl(hydroxy)phosphinyll-5-methoxy-2- nethyl-3-indolylacetate sodium salt.

B. l-[4'-chlorophenyl( hydroxy )phosphinyl1-5-methoxy- 2-methyl-3-indolylacetic acid mono sodium salt The above salt 1.0 g) in an atmosphere of dry nitro- ;en is dissplved in anhydrous trifluoroacetic acid (20 nl.) at 0, and left at this temperature overnight IOUI'S). The solvent is evaporated 0} reduced pressure caving l-[4'chlorophenyl(hydroxy )phosphinyl1-5- nethoxy-Z-3-indolylacetic acid mono sodium salt.

When potassium halide is substituted for sodium iolide in step (A) above, there is obtained tert-butyl-l- 4'-chlorophenyl(hydroxyJphosphinyl]-5-methoxy-2- nethyl-3-indolylacetate potassium salt, which may simlarly be cleaved as in step (B) above to yield l-[4'- hlorophenyl(hydroxy)phosphinyl]-5methoxy-2- iethyl-3-indolylacetic acid mono potassium salt.

EXAMPLE 11 l 4'-chlorophenyl(ethoxy)phosphinyl 5-methoxy-2- methyl-3-indolylacetic acid A solution of benzyl l-[4'-chlorophenyl(ethoxy) hosphinyl] -5-methoxy-2-methyl-3-indolylacetate 4.00 g.) in methanol (50 ml.) is hydrogenated at 40 ./in with 10% Ruthenium on carbon catalyst until 1 quivalent of hydrogen is absorbed. The mixture is fil- :red through supercel and evaporated under reduced ressure to yield l-[ 4" hlorophenyl(ethoxy)phosphinyl]-5-methoxy-2- iethyl3-indolylacetic acid.

When

enzyl l-[ 2-fluorophenyl( ethoxy )phosphinyl -5- methoxy-2-methyl-3-indolyl acetate enzyl l{4-methylthiophenyl(ethoxy)phosphinyl] 5 methoxy2-methyl-3-indolylacetate benzyl l-[4'-chlorophenyl(isopropoxy)phosphino1-5- methoxy-2-methyl-3-indolylacetate benzyl l-[diisopropoxyphosphinyl ]-5-methoxy-2- methyl-3-indolylacetate benzyl l-[ N,N-diethylamino(0-ethyl )phosphinyH-S- methoxy-2-methyI-Z-indolylacetate or benzyll -[4'-chlorophenyl(ethoxy)phospl1ino]-5- methoxy-Z-methyl-3-indolylacetate is substituted for benzyl chlorophenyl(ethoxy)phosphinyl]-5-methoxy-2- methylJ-indolylacetate there is obtained l-[2'-fluorophenyl(ethoxy)phosphinyl]-5-methoxy-2- methyl-3-indolylacetic acid l-[4'-methylthiophenyl(ethoxy)phosphinyl]'5- methoxy-Z-methyl-3-indolylacetic acid l-[4'-chlorophenyl(isopropoxy)phosphino1-5- methoxy-2-methyl-3-indolylacetic acid l-[diisopropoxyphosphinyl]-5-methyl-2-methyl-3- indolylacetic acid l-[N,N-diethylamino(O-ethyl)phosphinylj-S-methoxy- 2-methyl-3-indolylacetic acid or l-[4'-chlorophenyl(ethoxy)phosphino]-5-methoxy2- methyl-3-indolylacetic acid.

EXAMPLE l2 l-[4'-chlorophenyl(hydroxy)phosphinyl]-5-methoxy- 2-methyl-3-indolylacetic acid mono sodium salt l-[4-Chlorophenyl(ethoxy)phosphinyll-S-methoxy- 2-methyl-3-indolylacetic acid (2.11 g., 5.0 m. mole) is dissolved in a hot solution of dried sodium iodide (0.75 g., 5.0 rn. mole) in freshly distilled methyl ethyl ketone (25 ml. The solution is stirred and boiled under reflux in an atmosphere of dry nitrogen for 3 hours forming a precipitate of the product. Filtration, washing with acetone and drying in vacuo yields l-[4'- chlorophenyl(hydroxy)phosphinyl]-5-methoxy-2- methyl-3-indolylacetic acid mono sodium salt. When:

l-[4'-chlorophenyl(ethoxy)phosphinyl1-2-methyl-5- methoxy-6-chloroindolyl-3-acetic acid 1-[4-chlorophenyl(ethoxy)phosphinyH-Z-methyl-S- methylindolyl-3-acetic acid l-[4'-chlorophenyl(ethoxy)phosphinyl]-2-methyl-5- nitroindolyl3-acetic acid l-[4 '-chlorophenyl(ethoxy )phosphinyl-Z-methyl-S- dimethylaminoindolyl-3-acetic acid l-[O-ethyl(N,N-diethyl(amino)phosphinyll-Z-methyl- 5-dimethylaminoindolyl-3-acetic acid l-[4-chlorophenyl(ethoxy)phosphinyl]-2-metl1yl-5- (l-pyrrolidino)indolyl-3-acetic acid l-[4'-chlorophenyl(ethoxy)phosphinyl]-2-methyl-5- f'luoroindolyl-3-acetic acid l[4-chlorophenyl(ethoxy)phosphinyl]-2-methyl-5- acetylindolyl-3-acetic acid l-[4'-chlorophenyl(ethoxy)phosphinyll-Z-methyl-S- cyanoindolyl-3acetic acid l-[4'-chlorophenyl(ethoxy)phosphinyll-2-methyl-5- propenylindolyl]2-acetic acid l-[4'-chlorophenyl(ethoxy)phosphino1-2-methyl-5- methylindolyl-3-acetic acid l [4-chlorophenyl(ethoxy)phosphinol-Z-methyl-S- nitroindolyl-3-acetic acid l-[di-isopropoxy phosphino]-2-methyl-5-nitroindolyl- 3acetic acid 21 l-[4'-chlorophenyl(hydroxy)phosphinothioyl]-2- methyl--nitroindolyl-3-acetic acid di-sodium salt l-[4'-chlorophenyl( hydroxylphosphinothioyl1-2- methyl-5-dimethy1aminoindo1yl-3-acetic acid disodium salt l-[N,N-diethylamino(hydroxy)phosphinothioyl]-2- methyl-5-dimethylaminoindolyl-3-acetic acid disodium salt 1-[4'-chlorophenyl(hydroxy)phosphinothioyl1-2- methyl-5-(l-pyrrolidino)indolyl-3-acetic acid di- EXAMPLE 14 Tert-butyl l-diisopropoxyphosphinothioyl-S-methoxy-2-methyl- 3-indolylacetate 57% Sodium hydroxide oil dispersion (0.44 g., 10.5 m. mole) is added to a solution of tert-butyl 5-methoxy- 2-methyl-3-indolylacetate (2.75 g., 10.0 m. mole) in dry dimethyl formamide 15 ml.) with stirring and at a rate to keep the temperature 35-40. The mixture is stirred at 40 for 15 minutes to complete anion formation, then cooled to room temperature and ethyl 4- chlorophenylphosphonochloridothionate (2.81 g., l 1.0 m. mole) added at a rate to maintain a temperature not higher than 40. Stirring is continued at room tempera ture for 24 hours in an atmosphere of dry nitrogen, then the solvent is removed in a rotary evaporator at 40/0.l mm. and the crude product purified by chromatography over silica gel, yielding tert-butyl diisopropoxyphosphinothioyl-5-methoxy-2-methyl-3- indolylacetate.

1 claim: 1. A compound of formula 1 wherein R, is alkoxy, R is haloaryl, R is alkyl, R; is

alkoxy, M is hydroxy, X is oxygen, and n is l.

2. The compound of claim 1 wherein R is ethoxy, R is chlorophenyl, R is methyl, and R is methoxy.

3. A compound of formula R5\ CHZCOM P (X)n l 1 wherein R is alkoxy, R, is haloaryl, R is alkyl, R; is alkoxy, M is hydroxy, X is sulfur and n is l.

4. The compound of claim 3 wherein R is ethoxy, R is chlorophenyl, R is methyl and R is methoxy.

5. A compound of formula:

wherein R, is alkoxy, R is haloaryl, R is alkyl, R, is alkoxy, M is hydroxy, and n is 0.

6. The compound of claim 5 wherein R is ethoxy, R,

is chlorophenyl, R is methyl and R is methoxy. 

1. A COMPOUND OF FORMULA.
 2. The compound of claim 1 wherein R1 is ethoxy, R2 is chlorophenyl, R3 is methyl, and R5 is methoxy.
 3. A COMPOUND OF FORMULA
 4. The compound of claim 3 wherein R1 is ethoxy, R2 is chlorophenyl, R3 is methyl and R5 is methoxy.
 5. A COMPOUND OF FORMULA:
 6. The compound of claim 5 wherein R1 is ethoxy, R2 is chlorophenyl, R3 is methyl and R5 is methoxy. 